Provided herein are modulators of syndecan-2 and uses thereof, specifically to syndecan-2 antibodies and other syndecan-2 binding compositions for use in specific therapies and to methods of treatment and combination therapies using the modulators, e.g. antagonists, especially the antibodies.
The immune system has the ability to respond to pathogens using different mechanisms. If a pathogen succeeds in passing the first line of defence and enters the body, the innate immune response is activated, which involves a fast but largely non-specific response to infectious agents. The adaptive immune response is a slower but more specific response to pathogens.
Glycoproteins on the surface of T lymphocytes of the adaptive immune system, CD4 and CD8, give rise to the cells known as CD4+ T cells and CD8+ T cells. These CD molecules interact with other glycoproteins, major histocompatibility complex (MHC), on the surface of cells which then, in some cases, leads to the stimulation of the adaptive immune system. Antigen presenting cells, interact with T cell receptors, presenting antigens and resulting in CD4+ T cell activation. When activated via APCs, CD4+ T cells have the potential to differentiate into effector cells and have further immune functions.
Naïve CD4+ T cells have the potential to differentiate further into different types of effector cells with distinct functions depending on what pattern of signals (e.g. cytokines) they receive when the naïve cell is exposed to antigens. The most well described of these cell types are Th1, Th2, Th17 and Treg cells.
The immune system usually acts as a defence against potential pathogens, for example bacteria, viruses, protozoa, and fungi. It comprises various specific and non-specific defences, including several specific types of cells usually carried in the blood. Included among these are lymphocytes and in particular T cells, which are involved in the cell-mediated immune system. There are two major subtypes of T cells; namely cytotoxic T cells (Tc cells) and helper T cells (Th cells). T cells recognise antigens in combination with a major histocompatibility complex (MHC). Activation of Th cells causes the cells to release cytokines and other stimulatory signatures that stimulate the activity of macrophages, dendritic cells, neutrophils, natural killer cells or natural killer T-cells (NKT) aiding antigen clearance and also stimulate humoral response by stimulating B cells, with the B cells then producing antigen-specific antibodies.
In certain diseases, the immune system becomes overactive; these diseases including autoimmune diseases. In these diseases, the immune system does not correctly distinguish between “self” and “non-self”, and attacks parts of the body rather than or in addition to pathogens. Examples of such diseases include celiac disease, diabetes mellitus type 1, sarcoidosis, systemic lupus erythematosus (SLE), Sjögren's syndrome, Churg-Strauss syndrome, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), polymyositis (PM), and dermatomyositis (DM). New treatments for these and other auto-immune diseases are continually being sought.
Th17 cells are a sub-type of Th cells, which mainly produce their signature cytokine interleukin-17 (IL-17), in addition to the pro-inflammatory cytokines: IL-6, TNF, IL-21 and IL-22. Th17 cells are mainly involved in clearing pathogenic infection during host defense response by stimulating epithelial cells to produce cytokines, such as G-CSF and CXCL1, which act against bacteria and fungi and thus prevent opportunistic infections.
However, these cells are also involved in autoimmune diseases, creating tissue inflammation. The expression of IL-17 appears to be increased in human autoimmune diseases.
Chronic inflammation is also associated with development of cancer. Increases in inflammatory cytokines create an environment where a cancer cell is able to grow and spread to other tissues. Therefore, modulation of inflammatory T cells, such as Th17 cells, such as by modulators and inhibitors of syndecan-2, is useful in treatment of cancer.
Fibrosis in disease is the excessive formation of fibrous connective tissue. This, in some cases, is reparative, i.e. in response to an injury, where the connective tissue is known as scarring, or reactive, i.e. resulting from a disease condition.
Several diseases are associated with fibrosis, for example cystic fibrosis, cirrhosis and Crohn's disease, and in many cases the actual cause or initiation remains unknown.
Reparative fibrosis is regulated by a complex set of interactions, including profibrotic and antifibrotic cytokines and proteins. The proteins include profibrotic proteins, in particular transforming growth factor β (TGFβ) and connective tissue growth factor (CTGF) and antifibrotic proteins such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ).
TGFβ is generally considered to be the most important inducer of extracellular matrix and is considered to be a principle mediator in fibrosis. It activates and stimulates proliferation of fibroblasts, which synthesize extracellular matrix and collagen, forming the connective tissues.
TGFβ also induces the secretion of CTGF in endothelial cells and is considered a downstream mediator of the effects of TGFβ on fibroblasts.
Additionally TGFβ induces expression of the ED-A form of the matrix protein fibronectin (ED-A FN). This is required for TGFβ1-triggered enhancement of α-SMA and collagen type I expression.
The proinflammatory cytokine TNF-α, is antifibrotic as it suppresses the expression of matrix genes, and is expressed by macrophages during a normal wound healing response. Additionally proinflammatory cytokine IFN-γ released by T cells immediately after injury suppresses collagen synthesis.
In addition TGFβ is involved in the regulation of T helper (Th) cell differentiation. The presence or absence of TGFβ in combination with other cytokines (IL-6, IL-1, or IL-23) is critical for the developmental program of regulatory and effector T helper cells and for the final outcome in terms of anti-infective response, pathogenicity, or suppressive capacity. TGFβ inhibits Th1 and Th2 differentiation. By contrast, TGFβ in combination with IL-6, and IL-21 promotes the development of induced Foxp3+ regulatory T cells to Th17 cells.
TGFβ is released by leukocytes and stromal cells and in a few settings macrophages and dendritic cells too. Recent discoveries reinforce the idea that communication between fibroblasts, macrophages, and CD4 T cells integrates the processes of wound healing and host defence. Signals between macrophages and fibroblasts, under certain conditions, exacerbate, suppress, or reverse fibrosis. Fibroblasts and macrophages are activated by T cells, but their activation also engages negative feedback loops that reduce fibrosis by restraining the immune response, particularly when the Th2 cytokine IL-13 contributes to pathology. Thus the interactions among fibroblasts, macrophages, and CD4 T cells play general and critical roles in initiating, perpetuating, and resolving fibrosis in both experimental and clinical conditions. It is desired to provide improved anti-fibrosis therapies.
Macrophages also promote inflammation by recruiting and activating monocytes and neutrophils, provide antigens to CD4 T cells, and modulate cell responses with costimulation and cytokines. CD4 T cells coordinate the immune response with cytokines, enhancing neutrophil recruitment with IL-17A, activating macrophages with IL-4 and IL-13 or IFN-γ, and inducing collagen production by fibroblasts with IL-4, IL-13, and possibly TGF-β. The combination of activating signals from the inflammatory environment, macrophages, and CD4 T cells stimulate fibroblasts to proliferate and synthesize collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) that construct and remodel extracellular matrix and lead to fibrosis.
The syndecans are a family of heparan sulfate proteoglycans expressed on the cell surface of many mammalian cell types. The family members each comprise an extracellular domain and a transmembrane domain. The transmembrane domain is required for endogenous Syndecan-2 dimerization in vivo. Syndecan-2, encoded by the SDC2 locus and sometimes alternately referred to as SDC2, S2, CD362, or fibroglycan, is a member of this family that is primarily expressed in fibroblasts, developing neural tissue, mesenchymal stromal cells (MSCs) and mesenchymal cell types. Syndecan-2 has many roles to play in the body such as growth factor receptor activation and cell-cell adhesion in addition to its role in the immune system.